WO2013124403A1 - Composés pour le traitement d'une infection à parvovirus - Google Patents

Composés pour le traitement d'une infection à parvovirus Download PDF

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Publication number
WO2013124403A1
WO2013124403A1 PCT/EP2013/053526 EP2013053526W WO2013124403A1 WO 2013124403 A1 WO2013124403 A1 WO 2013124403A1 EP 2013053526 W EP2013053526 W EP 2013053526W WO 2013124403 A1 WO2013124403 A1 WO 2013124403A1
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WIPO (PCT)
Prior art keywords
amantadine
parvovirus
hydrogen
alkyl
compound
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PCT/EP2013/053526
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English (en)
Inventor
Nesya GORIS
Johan Neyts
Erwin Blomsma
Stefaan Wera
Jérôme VILLERS
Aino BILLIET
Joeri AUWERX
Veerle DEBEURME
Eleonora KISS
Chloë SWINNEN
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Okapi Sciences Nv
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Publication date
Application filed by Okapi Sciences Nv filed Critical Okapi Sciences Nv
Priority to IN5854DEN2014 priority Critical patent/IN2014DN05854A/en
Priority to EP13709160.9A priority patent/EP2817003A1/fr
Priority to RU2014138131A priority patent/RU2014138131A/ru
Priority to US14/380,515 priority patent/US20150018427A1/en
Priority to BR112014020597A priority patent/BR112014020597A2/pt
Priority to MX2014009950A priority patent/MX2014009950A/es
Priority to AU2013224031A priority patent/AU2013224031A1/en
Priority to CA2863851A priority patent/CA2863851A1/fr
Priority to JP2014558115A priority patent/JP2015508091A/ja
Priority to CN201380010169.9A priority patent/CN104220052A/zh
Publication of WO2013124403A1 publication Critical patent/WO2013124403A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to compounds for use in a method for the treatment or prevention of parvovirus infections in humans and warm-blooded animals, including feline panleukopenia virus (FPV) infections in felids, canine parvovirus type 2 (CPV-2) infections in canines, Minute Virus of Mice (MVM) infections in mice and B19 parvovirus infections in humans.
  • FV feline panleukopenia virus
  • CPV-2 canine parvovirus type 2
  • MMVM Minute Virus of Mice
  • Parvoviruses (family Parvoviridae) are small, non-enveloped, single-stranded DNA viruses that are mostly species specific. Parvoviridae are divided in the subfamilies of Densovirinae, infecting only invertebrates, and Parvovirinae, infecting vertebrates. The Parvovirinae subfamily is divided in the genera of Amdovirus, Bocavirus, Dependovirus, Erythrovirus and Parvovirus. In humans, human parvovirus B19 is the only member of the Parvoviridae known to be pathogenic. This B19 parvovirus is a member of the erythroviruses and is common and widespread.
  • B19 infection Manifestations of a B19 infection vary with the immunologic and hematologic status of the host. B19 exclusively infects humans and shows a pronounced tropism for erythroid precursors. B19 uses at least 3 cellular (co)- receptors for attachment and entry i.e. glycolipid globoside or group P antigen, ⁇ 5 ⁇ 1 - integrin and Ku80 auto-antigen.
  • IgG antibodies directed against human parvovirus B19 increases with age and ranges from 2-15% in children of 1 -5 years old, to 15-60% in children 6-19 years old, to 30-60% in adults, and to more than 85% in geriatric population. Women of childbearing age show an annual seroconversion rate of 1.5%.
  • antibodies are prevalent in the general population, viremia or presence of viral DNA is rare.
  • the frequency of B19 viremia in voluntary blood donors has been estimated at rates of 1 :167 to 1 :35,000. Transmission of infection occurs via the respiratory route or through blood- derived products administered parenterally or vertically from mother to fetus.
  • the spectrum of disease linked to B19 primarily involves infection in the healthy host manifested as:
  • Erythema infectiosum also called slapped cheek disease or fifth disease and the most prevalent manifestation of B19 in children;
  • parvovirus replication occurs only in rapidly dividing cells such as intestinal crypt epithelial cells, precursor cells in the bone marrow and myocardiocytes. Viral replication results in cell death and loss due to failure of mitosis.
  • Canine parvovirus type 2 was the second parvovirus described in dogs in 1978 after canine minute virus (CPV-1 ) in 1967, which is a member of the genus Bocavirus.
  • CPV-2 has 3 antigenic variants designated CPV-2a, CPV-2b and CPV-2c.
  • CPV-2 emerged as a dog pathogen likely through adaptation of a feline panleukopenia (FPV)-like parvovirus of wild carnivores.
  • FPV feline panleukopenia
  • CPV-2 variants are all able to infect cats and may even cause disease. In dog shelters and dog hospitals the prevalence of antibodies against CPV-2 can be as high as 58 to 67%.
  • CPV-2 The most characteristic clinical form induced by CPV-2 is represented by acute enteritis in puppies up to 6 months of age. Clinical signs occur after an incubation period of 3-7 days and consist of anorexia, depression, vomiting, mucoid or bloody diarrhea, dehydration and fever. Subclinical and unapparent infections as well as leukopenia are frequently observed. Mortality rates can be high in pups (70% and more) but are usually less than 1 % in adult dogs. Dogs infected with CPV-2 usually die from dehydration or secondary infection rather than the virus itself. CPV-2 spreads rapidly among dogs via fecal-oral route or through oronasal exposure to fomites contaminated by feces. Fecal excretion of the virus was detected as early as 3 days after infection and virus shedding may continue for a maximum period of 4 weeks after clinical or subclinical disease.
  • CPV-2 attenuated vaccines of canine origin are available in Europe and are licensed for administration to 4-12 week old puppies. In older animals, it is the common practice to give an annual booster vaccination. Complete cross-protection has been reported between all 3 antigenic variants. Data show that 93.7% of vaccinated dogs showed adequate antibody response more than 2 years following vaccination. Because no agent-specific treatment exists for CPV-2 enteritis, management of disease is limited to supportive care and requires hospitalization and aggressive treatment with crystalloid fluids, synthetic and natural colloids, correction of hypoglycemia and electrolyte disturbances, combination antimicrobials, antiemetics, analgesics, enteral nutritional support and anthelmintics.
  • G-CSF human granulocyte colony stimulating factor
  • FPV is known to infect, besides cats, also other members of the family Felidae, as well as raccoons, minks and foxes. FPV replication in dogs was seen only in some lymphoid tissues but not in the gut and virus was not shed. FPV causes a systemic infection in cats and the virus is transmitted fecal-orally (like CPV-2) and initially replicates in tissues of the oropharynx and is then distributed via a cell-free viremia to virtually all tissues. FPV infects lymphoid tissues and through cellular depletion can cause functional immunosuppression and lymphopenia. The bone marrow is affected as well and the virus has dramatic effect on virtually all myeloid cell populations.
  • FPV infection is diarrhea. Intra-uterine or perinatal infection may affect the central nervous system of the fetus leading to cerebellar ataxia and intention tremor in affected kittens. Although FPV affects cats of all ages, kittens are most susceptible with a mortality rate as high as 90% and more.
  • FPV vaccines are available for administration (at 8-9 weeks of age) and provide solid immunity against the disease.
  • a booster vaccine is recommended 1 year after the kitten vaccination course and with intervals of 3 years.
  • cats having responded to FPV vaccination maintained a solid immunity to FPV for at least 7 years in the absence of booster vaccinations or natural challenge.
  • Disease management consists mainly of supportive therapy and good nursing mostly including restoration of fluid and electrolytes.
  • Antibiotics, anti-emetics, vitamin complexes and eventual plasma or whole blood transfusion and parenteral nutrition may be needed in anorexic cats.
  • Feline recombinant IFN-omega inhibits FPV replication in cell culture but so far no data are available on its efficacy in FPV infected cats.
  • Amantadine is indicated for various conditions that can be treated by NMDA receptor antagonists including the treatment of idiopathic Parkinson's disease (Paralysis Agitans), postencephalitic Parkinsonism, and symptomatic Parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication. Amantadine is also used for the prophylaxis and treatment of influenza A virus. However, the use of amantadine for the treatment or prevention of parvovirus infection has not been suggested in the art.
  • the present invention relates to the use of a compound of the amantadine family for the treatment or prevention of a parvovirus infection in a human or animal.
  • the invention provides a compound of the amantadine family, or a solvate, hydrate, pharmaceutically acceptable salt or veterinary acceptable salt thereof, or a composition comprising one or more of such compounds for use in a method for the treatment or prevention of a parvovirus infection in a human or a warmblooded animal.
  • the compound of the amantadine family is a compound of formula (I), or a stereoisomer, salt, solvate or hydrate thereof
  • R 1 is selected from amino, aminoCi -6 alkyl, Ci -6 alkylamino and Ci- 6 alkylaminoCi- 6 alkyl, and R 2 and R 6 are hydrogen; or wherein R 1 is hydrogen, R 2 is selected from amino, aminoCi -6 alkyl or Ci -6 alkylamino, and R 6 is hydrogen or Ci -6 alkyl; and
  • R 3 , R 4 and R 5 are each independently selected from hydrogen, Ci -6 alkyl and hydroxyl; for use in a method for the treatment or prevention of a parvovirus infection in a human or a warm-blooded animal.
  • R 1 is amino and R 2 and R 6 are hydrogen; or R 1 is hydrogen, R 2 is selected from amino, aminoCi -6 alkyl or Ci -6 alkylamino, and R 6 is hydrogen or Ci -6 alkyl; and R 3 , R 4 and R 5 are hydrogen or Ci -6 alkyl.
  • R 2 is amino.
  • R 6 is hydrogen.
  • the compound of the amantadine family is a compound of formula (la), or a stereoisomer, salt, solvate or hydrate thereof;
  • R 1 is amino, and R 2 is hydrogen; or wherein R 1 is hydrogen and R 2 is selected from amino, aminoCi -6 alkyl or Ci -6 alkylamino; and R 3 , R 4 and R 5 are each independently selected from hydrogen and Ci -6 alkyl. In yet further embodiments, R 2 is amino.
  • said compound is selected from amantadine, memantine, 2- adamantylamine, 2-methyladamantan-2-amine, and 2-ethyladamantan-2-amine, or a solvate, hydrate, pharmaceutically acceptable salt or veterinary acceptable salt thereof.
  • the compound is selected from amantadine, memantine, and 2- adamantylamine, or a solvate, hydrate, pharmaceutically acceptable salt or veterinary acceptable salt thereof.
  • the compound is amantadine or amantadine hydrochloride.
  • the compound is memantine.
  • the compound is for use in a method for lowering the viral load of said parvovirus.
  • said parvovirus infection is caused by a virus of the subfamily Parvovirinae.
  • the compound is for use in a method for the treatment or prevention of a human parvovirus B19 infection in a human.
  • said warm-blooded animal is a canine.
  • the compound is for use in a method for the treatment or prevention of a canine parvovirus infection in a canine.
  • said warm-blooded animal is a felid.
  • the compound is for use in a method for the treatment or prevention of a feline panleukopenia virus infection in a felid.
  • composition comprising one or more compounds of formula (I), or a solvate, pharmaceutically acceptable salt or veterinary acceptable salt thereof;
  • R 1 is selected from amino, aminoCi -6 alkyl, Ci -6 alkylamino and Ci- 6 alkylaminoCi- 6 alkyl, and R 2 and R 6 are hydrogen; or wherein R 1 is hydrogen, R 2 is selected from amino, aminoCi -6 alkyl or Ci -6 alkylamino, and R 6 is hydrogen or Ci -6 alkyl; and
  • R 3 , R 4 and R 5 are each independently selected from hydrogen, Ci -6 alkyl and hydroxyl; for use in a method for the treatment or prevention of a parvovirus infection in a human or a warm-blooded animal.
  • Figure 1 Structure formula of various compounds of the amantadine family.
  • Figure 2 Structure formula of salts of various compounds of the amantadine family.
  • parvovirus refers to a virus which is a member of the family Parvoviridae, preferably from the subfamily Parvoririnae.
  • exemplary parvoviruses include, but are not limited to, feline panleukopenia virus, canine parvovirus type 2, human parvovirus B19, minute virus of mice, bovine parvovirus, canine parvovirus, chicken parvovirus and goose parvovirus.
  • the term "puppy” refers to a (domestic) dog which is about 3 years old or less, alternately about 2 years old or less, alternately about 1 year old or less
  • the term “kitten” refers to a (domestic) cat which is about 3 years old or less, alternately about 2 years old or less, alternately about 1 year old or less.
  • child refers to a human between the stages of birth and puberty, preferably a human about 12 years or less.
  • warm-blooded animal includes companion animals, such as dogs and cats; domestic animals, such as horses, cattle, sheep, swine, goats, rabbits and chickens; and laboratory animals such as mice, rats and monkeys.
  • the warmblooded animal is mammal, more preferably a companion animal such as a cat or a dog.
  • alkyl by itself or as part of another substituent, refers to a straight or branched saturated hydrocarbon group joined by single carbon-carbon bonds having 1 to 6 carbon atoms, for example 1 to 5 carbon atoms, for example 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • Ci -6 alkyl means an alkyl of one to six carbon atoms.
  • Examples of Ci -4 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and ie f-butyl.
  • Ci -6 alkylene by itself or as part of another substituent, refers to Ci -6 alkyl groups that are divalent, i.e., with two single bonds for attachment to two other groups.
  • Alkylene groups may be linear or branched and may be substituted as indicated herein.
  • Non-limiting examples of alkylene groups include methylene (-CH 2 -), ethylene (- CH2-CH2-), methylmethylene (-CH(CH 3 )-), 1 -methyl-ethylene (-CH(CH 3 )-CH 2 -), n- propylene (-CH 2 -CH 2 -CH 2 -), 2-methylpropylene (-CH 2 -CH(CH 3 )-CH 2 -), 3-methylpropylene (-CH 2 -CH 2 -CH(CH 3 )-), n-butylene (-CH 2 -CH 2 -CH 2 -CH 2 -), 2-methylbutylene (-CH 2 - CH(CH 3 )-CH 2 -CH 2 -), 4-methylbutylene (-CH 2 -CH 2 -CH 2 -CH(CH 3 )-), pentylene and its chain isomers, hexylene and its chain isomers.
  • amino by itself or as part of another substituent, refers to -NH 2.
  • aminoCi- 6 alkyr' by itself or as part of another substituent, refers to a group of formula -R'-NH 2 wherein R' is Ci -6 alkylene as defined herein.
  • Ci- 6 alkylaminoCi- 6 alkyl refers to a group of formula -R j -NR k R' wherein R j is Ci -6 alkylene as defined herein, R k is hydrogen or Ci -6 alkyl as defined herein, and R 1 is Ci -6 alkyl as defined herein.
  • Ci -6 alkylamino by itself or as part of another substituent, refers to the group -NR m R n wherein R m is Ci -6 alkyl as defined herein and R n is hydrogen or Ci -6 alkyl as defined herein.
  • the compounds of formula (I) may have one or more centers of chirality and may exist as stereochemically isomeric forms.
  • stereoisomer as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which the compounds of formula (I) may possess.
  • pharmaceutically acceptable salts or "veterinary acceptable salts” as used herein means the therapeutically active non-toxic addition salt forms which the compounds of formula are able to form and which may conveniently be obtained by treating the base form of such compounds with an appropriate base or acid.
  • pharmaceutically acceptable acid and base addition salts as mentioned herein are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds according to the present invention are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric
  • solvate is used herein to describe a molecular complex comprising a particular compound and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • hydrate is employed when said solvent is water.
  • amantadine and compounds related to amantadine show a surprisingly strong inhibition of parvovirus replication.
  • compounds of the amantadine family such as amantadine, memantine, 2- adamantylamine, 2-methyladamantan-2-amine, and 2-ethyladamantan-2-amine inhibit replication of human parvovirus B19, feline panleukopenia virus (FPV), canine parvovirus type 2 (CPV-2) and minute virus of mice (MVM). Therefore, these compounds are useful for the treatment or prevention of parvovirus infections in humans and animals. More particularly, these compounds are useful for lowering the parvovirus viral load in humans and animals.
  • compounds of the amantadine family are typically compounds of formula (I), stereoisomers, salts, solvates or hydrates thereof;
  • R 1 is selected from amino, aminoCi -6 alkyl, Ci -6 alkylamino and Ci- 6 alkylaminoCi- 6 alkyl, and R 2 and R 6 are hydrogen; preferably R 1 is selected from amino, aminoCi -4 alkyl, Ci -4 alkylamino and preferably R 1 is selected from amino, aminoCi -3 alkyl, Ci -3 alkylamino and Ci- 3 alkylaminoCi- 3 alkyl; preferably R 1 is selected from amino, aminomethyl, 1 -amino-1 -methyl-methyl, or methylamino; more preferably R 1 is selected from amino, aminomethyl, or methylamino; or
  • R 1 is hydrogen
  • R 2 is selected from amino, aminoCi -6 alkyl or Ci -6 alkylamino
  • R 6 is hydrogen or Ci -6 alkyl
  • R 2 is selected from amino, aminoCi -4 alkyl, Ci -4 alkylamino and Ci -4 alkylaminoCi -4 alkyl
  • R 2 is selected from amino, aminoC-i- 3 alkyl, Ci -3 alkylamino and Ci -3 alkylaminoCi -3 alkyl
  • R 2 is selected from amino, aminomethyl, 1 -amino-1 -methyl-methyl, or methylamino
  • R 2 is selected from amino, aminomethyl, or methylamino
  • most preferably R 2 is amino
  • R 3 , R 4 and R 5 are each independently selected from hydrogen, Ci -6 alkyl and hydroxyl; preferably R 3 , R 4 and R 5 are each independently selected from hydrogen, Ci -4 alkyl and hydroxyl, for example R 3 , R 4 and R 5 are each independently selected from hydrogen, d. 3 alkyl and hydroxyl, for example R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, isopropyl and hydroxyl.
  • R 1 , R 2 and R 6 have the same meaning as that defined above
  • R 3 is selected from hydrogen, Ci -6 alkyl or hydroxyl, preferably from hydrogen, Ci -4 alkyl and hydroxyl, for example from hydrogen, methyl and hydroxyl
  • R 4 and R 5 are independently selected from hydrogen or Ci -6 alkyl, preferably from hydrogen, or Ci -4 alkyl.
  • R 2 and R 6 are hydrogen.
  • R 3 , R 4 and R 5 are each independently selected from hydrogen and Ci -6 alkyl. In certain embodiments, R 3 , R 4 and R 5 are each independently selected from hydrogen and Ci -4 alkyl, for example R 3 , R 4 and R 5 are each independently hydrogen or methyl.
  • R 1 is amino and R 2 and R 6 are hydrogen; or R 1 is hydrogen, R 2 is selected from amino, aminoCi -6 alkyl or Ci -6 alkylamino, and R 6 is hydrogen or Ci -6 alkyl; and R 3 , R 4 and R 5 are each independently selected from hydrogen and Ci -6 alkyl.
  • R 1 is amino and R 2 and R 6 are hydrogen; or R 1 is hydrogen, R 2 is amino, and R 6 is hydrogen or Ci -6 alkyl; and R 3 , R 4 and R 5 are each independently selected from hydrogen and Ci -6 alkyl.
  • R 1 is amino
  • R 2 and R 6 are hydrogen
  • R 3 , R 4 and R 5 are each independently hydrogen or Ci -6 alkyl, for example hydrogen or methyl.
  • R 1 is hydrogen
  • R 2 is amino
  • R 6 is hydrogen or Ci -6 alkyl
  • R 3 , R 4 and R 5 are each independently hydrogen or Ci -6 alkyl, for example hydrogen or methyl. If R 6 is Ci -6 alkyl, R 6 preferably is Ci -4 alkyl, more preferably Ci -3 alkyl, and most preferably methyl or ethyl.
  • R 6 is hydrogen. Accordingly, in these embodiments, the compounds of the amantadine family are compounds of formula (la)
  • R 1 , R 2 , R 3 , R 4 and R 5 have the same meaning as that defined above.
  • amantadine hydrochloride amantadine hydrochloride
  • rimantadine Another member of the amantadine family is rimantadine, which is used in the treatment and prevention of influenza A and sold under the name Flumadine ® .
  • the present invention relates to the use of compounds of the amantadine family and compositions comprising such compounds in the prevention and treatment of a parvovirus infection in a human or warm-blooded animal.
  • the invention provides a compound from the amantadine family for use in a method for the treatment or prevention of a parvovirus infection in a human or a warm-blooded animal as well as well as methods for the treatment and/or prevention of a parvovirus infection involving the administration of said compounds.
  • the compound of the amantadine family envisaged in the context of the present invention is selected from amantadine, rimantadine, memantine, 3-amino-1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine, 2-adamantylamine, 2- methyladamantan-2-amine, 2-ethyladamantan-2-amine, or solvates, pharmaceutically acceptable salts or veterinary acceptable salts thereof.
  • the compound of the amantadine family envisaged in the context of the present invention is selected from amantadine, memantine, 3-amino-1 -amantadol, 1 -adamantanemethylamine, N-methyl-1 - adamantylamine, 2-adamantylamine, 2-methyladamantan-2-amine, and 2- ethyladamantan-2-amine, or solvates, pharmaceutically acceptable salts or veterinary acceptable salts thereof.
  • the compound of the amantadine family envisaged in the context of the present invention is selected from amantadine, memantine, 3-amino-1 -amantadol, 1 -adamantanemethylamine, N-methyl-1 - adamantylamine and 2-adamantylamine, or solvates, pharmaceutically acceptable salts or veterinary acceptable salts thereof.
  • the compound of the amantadine family envisaged in the context of the present invention is selected from amantadine, memantine and 2-adamantylamine, 2-methyladamantan-2-amine, and 2-ethyladamantan-2-amine, or solvates, pharmaceutically acceptable salts or veterinary acceptable salts thereof.
  • the compound of the amantadine family is selected from amantadine, memantine and 2-adamantylamine, or solvates, pharmaceutically acceptable salts or veterinary acceptable salts thereof.
  • the compound of the amantadine family is 2-methyladamantan-2- amine or 2-ethyladamantan-2-amine, or solvates, pharmaceutically acceptable salts or veterinary acceptable salts thereof.
  • the compounds amantadine, rimantadine, memantine, 3-amino-1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine, 2-adamantylamine, 2- methyladamantan-2-amine and 2-ethyladamantan-2-amine are represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X), respectively ( Figure 1 ).
  • the compound envisaged for the treatment of a parvovirus infection according to the present invention is amantadine or a solvate or pharmaceutically or veterinary acceptable salt thereof.
  • the compound is rimantadine or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of is memantine or a solvate or pharmaceutically or veterinary acceptable salt thereof.
  • the invention provides the use 3-amino- 1 -amantadol or a solvate or pharmaceutically or veterinary acceptable salt thereof for the treatment or prevention of a parvovirus infection.
  • the compound is 1 -adamantanemethylamine or a solvate or pharmaceutically or veterinary acceptable salt thereof.
  • the compound is N-methyl-1 -adamantylamine or a solvate or pharmaceutically or veterinary acceptable salt thereof. In certain embodiments, the compound is 2-adamantylamine or a solvate or pharmaceutically or veterinary acceptable salt thereof. In certain embodiments, the compound is 2-methyladamantan-2- amine or a solvate or pharmaceutically or veterinary acceptable salt thereof. In certain embodiments, the compound is 2-ethyladamantan-2-amine or a solvate or pharmaceutically or veterinary acceptable salt thereof.
  • the pharmaceutically (or veterinary) acceptable salt of the compounds envisaged for use in the methods of the present invention is an acid addition salt.
  • the acid addition salt is a hydrochloride or a sulphate.
  • Hydrochlorides may be prepared by mixing the compound according to the present invention with hydrochloric acid. Conversion of the compounds according to the present invention into acid addition salts typically increases the solubility of the compounds in water, and facilitates release of the compound in the gastrointestinal tract. Furthermore, conversion into an acid addition salt may prolong the shelf-life of the compounds envisaged for use in the compositions according to the invention.
  • the pharmaceutically (or veterinary) acceptable salt of the compounds envisaged in the context of the present invention is selected from amantadine hydrochloride, rimantadine hydrochloride, memantine hydrochloride, 3-amino-1 -amantadol hydrochloride, 1 -adamantanemethylamine hydrochloride, N-methyl-1 -adamantylamine hydrochloride, 2-adamantylamine hydrochloride, 2-methyladamantan-2-amine hydrochloride, and 2-ethyladamantan-2-amine hydrochloride, which are represented by formula (Ma), (Ilia), (IVa), (IVa), (Va), (Via), (Vila), (Villa), (IXa) and (Xa), respectively ( Figure 2).
  • the pharmaceutically (or veterinary) acceptable salt of the compounds envisaged in the context of the present invention is selected from amantadine hydrochloride, memantine hydrochloride, 3-amino-1 -amantadol hydrochloride, 1 - adamantanemethylamine hydrochloride, N-methyl-1 -adamantylamine hydrochloride and 2-adamantylamine hydrochloride, 2-methyladamantan-2-amine hydrochloride, and 2- ethyladamantan-2-amine hydrochloride.
  • the pharmaceutically (or veterinary) acceptable salt is selected from amantadine hydrochloride, memantine hydrochloride, 2-adamantylamine hydrochloride, 2-methyladamantan-2-amine hydrochloride, and 2-ethyladamantan-2-amine hydrochloride.
  • the pharmaceutically (or veterinary) acceptable salt is selected from amantadine hydrochloride, memantine hydrochloride and 2-adamantylamine hydrochloride.
  • the compound envisaged for the treatment or prevention of a parvovirus infection according to the present invention is amantadine, amantadine hydrochloride, rimantadine, memantine, 3-amino-1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine or 2-adamantylamine HCI, for example amantadine, amantadine hydrochloride, memantine or 2-adamantylamine HCI.
  • the compound according to the present invention is amantadine hydrochloride.
  • the pharmaceutically (or veterinary) acceptable salt of the compounds envisaged in the context of the present invention is selected from amantadine sulphate, rimantadine sulphate, memantine sulphate, 3-amino-1 -amantadol sulphate, 1 - adamantanemethylamine sulphate, N-methyl-1 -adamantylamine sulphate, 2- adamantylamine sulphate, 2-methyladamantan-2-amine sulphate, and 2-ethyladamantan- 2-amine sulphate.
  • the pharmaceutically (or veterinary) acceptable salt of the compounds envisaged in the context of the present invention is selected from amantadine sulphate, memantine sulphate, 2-adamantylamine sulphate, 2- methyladamantan-2-amine sulphate, and 2-ethyladamantan-2-amine sulphate.
  • the pharmaceutically (or veterinary) acceptable salt is selected from amantadine sulphate, memantine sulphate, 3-amino-1 -amantadol sulphate, 1 - adamantanemethylamine sulphate, N-methyl-1 -adamantylamine sulphate and 2- adamantylamine sulphate.
  • the pharmaceutically (or veterinary) acceptable salt is selected from amantadine sulphate, memantine sulphate and 2- adamantylamine sulphate.
  • the present invention envisages the prevention and/or treatment of parvovirus infections in animals and humans by administering combinations of the compounds disclosed herein and other active ingredients. Such combinations may be administered simultaneously or separately.
  • the invention provides formulations in which the compounds described herein are combined with other active ingredients, such as non-steroidal anti-inflammatory drugs, interferons, G-CSFs etc.
  • the invention provides a compound of the amantadine family, or a solvate, pharmaceutically or veterinary acceptable salt thereof, in admixture with one or more other active ingredients, for use in a method for the treatment or prevention of a parvovirus infection, and/or for lowering parvovirus viral load.
  • the present invention relates to the use of (compositions comprising) one or more compounds of the amantadine family in the treatment or prevention of a parvovirus infection which is caused by a virus of the subfamily Parvovirinae, such as MVM, FPV, CPV-2 and parvovirus B19.
  • a virus of the subfamily Parvovirinae such as MVM, FPV, CPV-2 and parvovirus B19.
  • the present invention relates to the (compositions comprising) one or more compounds of the amantadine family for use in a method for lowering the viral load of a virus of the subfamily Parvovirinae and/or methods for lowering the viral load of a virus of the subfamily Parvovirinae comprising administering to a subject in need thereof, an effective amount of (compositions comprising) one or more compounds of the amantadine family so as to reduce the viral load of said virus.
  • the envisaged compounds are effective against human parvovirus B19, which is the only member of the Parvoviridae family known to be pathogenic in humans.
  • the present invention provides in the use of (compositions comprising) a compound of the family of amantadine in the treatment or prevention of a human parvovirus B19 infection in a human. Children are typically more susceptible to parvovirus infection than adults. Parvovirus infection during pregnancy may lead to fetal death.
  • the invention provides for the treatment of pregnant women and/or children, more preferably for the treatment and prevention of a parvovirus infection, more preferably an infection with a human parvovirus B19 in a child of an age above 1 year.
  • the compound according to the present invention is preferably memantine or memantine hydrochloride.
  • the compound according to the present invention is preferably memantine, rimantadine, memantine hydrochloride or rimantadine hydrochloride, more preferably memantine or memantine hydrochloride.
  • parvovirus infection may have various expressions such as erythema infectiosum (also known as "fifth disease"), (seronegative) arthritis and anemia.
  • the present method envisages the use of a (composition comprising a) compound of the amantadine family in the treatment of one or more symptoms selected from erythema infectiosum, arthritis and anemia.
  • the invention further relates to the use of (a composition comprising) a compound of the amantadine family in the treatment or prevention of a parvovirus infection in an animal, and/or for the reduction of parvovirus viral load in an animal.
  • the animal is a warm-blooded animal.
  • said animal is a carnivorous animal.
  • said animal is a companion animal such as a canine or a felid or a laboratory animal such as a mouse.
  • the compound according to the present invention are envisaged for use in a method for the treatment or prevention of a canine parvovirus infection in a canine, and/or for the reduction of parvovirus viral load in a canine.
  • said canine parvovirus infection is caused by a virus selected from canine parvovirus type 2 (CPV-2) and canine minute virus (CPV-1 ).
  • the CPV-2 virus is CPV-2a, CPV-2b or CPV-2c.
  • said canine is a dog. Mortality rates of CPV-2 infected dogs are particularly high in pups. Accordingly, particular embodiments of the invention relate to the treatment or prevention of parvovirus infections in puppies.
  • the compounds and compositions comprising the compounds described herein are further envisaged for use in the treatment or prevention of a feline panleukopenia virus (FPV) infection in a felid, and/or for the reduction of FPV viral load in a felid.
  • FPV feline panleukopenia virus
  • the felid is a cat.
  • FPV affects cats of all ages, kittens are most susceptible. Accordingly, in further embodiments, the cat is a kitten.
  • the invention relates to the treatment and prevention of a Minute Virus of Mice (MVM) in a rodent, and/or for the reduction of MVM viral load in a rodent such as a mouse, rat or hamster.
  • MVM infections are a common problem in laboratory mice breeding. Therefore, in preferred embodiments, the rodent is a mouse.
  • the invention also envisages the prevention and treatment of parvovirus infections, and/or the reduction of parvovirus viral load, using one or more compounds of the amantadine family provided in a composition.
  • the present invention provides a composition comprising one or more compounds of the amantadine family, or a solvate, pharmaceutically or veterinary acceptable salt thereof, for use in a method for the treatment or prevention of a parvovirus infection, and/or for use in a method for the reduction of parvovirus viral load.
  • the composition may comprise two or more compounds of the amantadine family, or a solvate, pharmaceutically or veterinary acceptable salt thereof.
  • the composition comprises two or more compounds selected from amantadine, rimantadine, memantine, 3-amino-1 - amantadol, 1 -adamantanemethylamine, N-methyl-1 -adamantylamine, 2-adamantylamine, 2-methyladamantan-2-amine, and 2-ethyladamantan-2-amine, or a pharmaceutically or veterinary acceptable salt thereof.
  • the composition comprises two or more compounds selected from amantadine, memantine, 2-adamantylamine, 2- methyladamantan-2-amine, and 2-ethyladamantan-2-amine, or a pharmaceutically or veterinary acceptable salt thereof.
  • the composition comprises two or more compounds selected from amantadine, memantine, 3-amino-1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine and 2-adamantylamine or a pharmaceutically or veterinary acceptable salt thereof.
  • the composition comprises two or more compounds selected from amantadine, memantine and 2-adamantylamine or a pharmaceutically or veterinary acceptable salt thereof.
  • compositions used in the treatment and/or prevention of a parvovirus infection as described herein will comprise in addition to one or more compounds from the amantadine family, and optionally other active ingredients, one or more pharmaceutically or veterinary acceptable carriers or excipients. Such compositions are typically also referred to as pharmaceutical compositions.
  • the present invention also encompasses pharmaceutical composition comprising one or more compounds of the amantadine family, or a solvate, pharmaceutically acceptable salt or veterinary acceptable salt thereof, for use in a method for the treatment or prevention of a parvovirus infection in a human or a warm-blooded animal, and/or for use in a method for the reduction of the parvovirus viral load in a warm-blooded animal.
  • pharmaceutically acceptable carrier or "veterinary acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier or veterinary acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable carriers are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol, benzyl alcohol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol, benzyl alcohol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 ⁇ , namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • the present invention also encompasses pharmaceutical composition
  • pharmaceutical composition comprising one or more compounds of formula (I), or a stereoisomer, salt, solvate or hydrate thereof, for use in a method for the treatment or prevention of a parvovirus infection in a human or a warm-blooded animal.
  • the pharmaceutical composition comprises one or more compounds selected from amantadine, rimantadine, memantine, 3-amino-1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine, 2-adamantylamine2- methyladamantan-2-amine, and 2-ethyladamantan-2-amine.
  • the pharmaceutical composition comprises one or more compounds selected from amantadine, memantine, 2-adamantylamine, 2-methyladamantan-2-amine, and 2- ethyladamantan-2-amine.
  • the pharmaceutical composition comprises one or more compounds selected from amantadine, rimantadine, memantine, 3-amino-1 -amantadol, 1 -adamantanemethylamine, N-methyl-1 -adamantylamine or 2- adamantylamine, for example amantadine or memantine or combination thereof.
  • the present invention provides methods for the treatment and/or prevention of a parvovirus infection in an animal or human, and/or for the reduction of parvovirus viral load in an animal or human.
  • the methods of treatment encompass administration of the compounds or compositions described herein to a human or animal suffering from a parvovirus infection.
  • the animal or human may have been diagnosed as suffering from a parvovirus infection or may be identified as having parvovirus associated symptoms.
  • the methods are envisaged for the treatment of human patients identified has having B19 parvovirus associated symptoms and/or patients identified as infected or carrying B19 parvovirus or characterized by the presence of antibodies to B19 parvovirus.
  • the methods are envisaged for the treatment of animal of a felid suffering from feline panleukopenia virus infection.
  • the methods are envisaged for the treatment of felids identified has having panleukopenia virus infection associated symptoms and/or felids identified as infected or carrying panleukopenia virus or characterized by the presence of antibodies to panleukopenia virus.
  • the methods of treatment involve the administration of an effective amount of the compounds or compositions described herein.
  • compositions comprising a) compound of the amantadine family in the methods for treatment or prevention of a parvovirus infection may depend on the severity of the infection and characteristics of the patient, such as age and/or weight.
  • the compound or compositions may be administered once or twice per day, for at least 3, 4, 5, 6 or 7 days.
  • the composition can be in the form of tablets formulated in conventional manner.
  • tablets and capsules for oral administration can contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (e.g., magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated according to methods well known in the art.
  • composition described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example.
  • formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can contain conventional additives, such as suspending agents, such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin, glucose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminum stearate gel, emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol; and preservatives, such as methyl or propyl p-hydroxybenzoate and sorbic acid.
  • suspending agents such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methyl
  • liquid forms in which the compositions described herein may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous suspensions and/or elixirs are desired for oral administration
  • the compounds described herein can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • compositions described herein can be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing, and/or dispersing agents.
  • the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
  • the present invention also provides the use of (a composition comprising) one or more compounds selected from the amantadine family such as but not limited to amantadine, rimantadine, memantine, 3-amino1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine, 2-adamantylamine, 2- methyladamantan-2-amine, and 2-ethyladamantan-2-amine, or a solvate or pharmaceutically or veterinary acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a parvovirus infection in a human or a warm-blooded animal.
  • amantadine family such as but not limited to amantadine, rimantadine, memantine, 3-amino1 -amantadol, 1 - adamantanemethylamine, N-methyl-1 -adamantylamine, 2-adamantylamine, 2- methyladamant
  • Example 1 Inhibition of feline panleukopenia virus and canine parvovirus 2c replication by amantadine, amantadine hydrochloride (HCI), 2-adamantylamine HCI, 3-amino-1 - amantadol, N-methyl-1 -adamantylamine, 1 -adamantanemethylamine, rimantadine and memantine in cell culture
  • DPBS Dulbecco's phosphate buffered saline
  • CrFK Crandell Reese Feline Kidney cells were grown in Dulbecco minimum essential medium (DMEM, Life Technologies) containing 1 % sodium bicarbonate (Life Technologies), 1 % L- Glutamine (Life Technologies) and 5% fetal calf serum (FCS, Biochrom).
  • TCID 50 of feline panleukopenia virus FPV
  • 10 TCID 50 canine parvovirus 2c CPV-2c
  • 20,000 CrFK cells Infected cells without any added compound were used as positive controls (virus control) and uninfected cells were used as negative controls (cell control). The cells were incubated for 4 days and viral cytopathogenic effect (CPE) was scored visually.
  • CPE viral cytopathogenic effect
  • Example 2 Inhibition of feline panleukopenia virus and canine parvovirus 2c production and viral DNA production in cell culture by amantadine, amantadine hydrochloride (HCI), and memantine.
  • amantadine amantadine hydrochloride (HCI)
  • memantine memantine
  • DPBS Dulbecco's phosphate buffered saline
  • DMEM Dulbecco minimum essential medium
  • FCS fetal calf serum
  • FPV or CPV-2c DNA was extracted using the QIAamp DNA extraction kit (Qiagen).
  • the extracted FPV DNA was detected by a real time PCR using the Taqman Fast Universal mastermix (Life Technologies) and the standard Fast cycling protocol using the StepOnePlus real time device (Applied Biosystems).
  • a real time PCR using the Taqman Fast Universal mastermix (Life Technologies) and the standard Fast cycling protocol using the StepOnePlus real time device (Applied Biosystems).
  • an optimized 900 nM of each forward and reverse primer was used and 250 nM FAM-BHQ1 labeled probe as published by Decaro et al. (J. Virol. Methods 2008, 147, 67-71 ).
  • EC 50 values were determined as the concentration of compound that inhibited 50% of the viral DNA.
  • amantadine amantadine hydrochloride (HCI) and memantine that effectively inhibits 50% of FPV and CPV-2c DNA production (EC 50 ) as measured by quantitative PCR is given in Table 2.
  • Amantadine HCI was found to be the most effective in viral DNA reduction.
  • CPV-2c and FPV titers Reduction of CPV-2c and FPV titers under increasing concentrations of amantadine hydrochloride (HCI) and memantine are shown in Table 3a and 3b, respectively.
  • Viral titers are determined by titration of the produced virus on CrFK cells and incubated for 5 days. The obtained titers where compared with the control (virus production without addition of compound). Amantadine HCI was found to be the most efficient in reduction of FPV and CPV-2c production.
  • Example 3 Inhibition of feline panleukopenia virus and canine parvovirus 2c production and viral DNA production in cell culture by 2-methyladamantan-2-amine hydrochloride and 2-ethyladamantan-2-amine hydrochloride.
  • 2-methyladamantan-2-amine HCI and 2-ethyladamantan-2-amine HCI were dissolved in Dulbecco's phosphate buffered saline (DPBS) at a concentration of 10 mM.
  • DPBS Dulbecco's phosphate buffered saline
  • the concentration of 2-methyladamantan-2-amine HCI and 2-ethyladamantan-2-amine HCI that effectively inhibits 50% of FPV and CPV-2c virus and DNA production (EC 50 ) as measured by a cytopathic effect (CPE) visual scoring assay and by quantitative PCR is given in Table 4a and Table 4b, respectively.
  • CPE cytopathic effect
  • Example 4 Treatment of mice infected with Minute Virus of Mice with amantadine hydrochloride Severe combined immunodeficient (SCID) mice were infected with a preparation of Minute Virus of Mice type p (MVMp) by intraperitoneal inoculation. Whereas MVMp is not lethal to healthy mice, administration of high titers of MVMp resulted in high mortality rates in SCID mice as shown in Table 5. However, treatment of the mice from day 0 of infection onwards with 10 mg/kg amantadine HCI resulted in a significant survival of the mice.
  • SCID Severe combined immunodeficient mice were infected with a preparation of Minute Virus of Mice type p
  • Example 5 Treatment with amantadine hydrochloride of dogs naturally infected with canine parvovirus type 2
  • a beagle puppy of 2 months of age with clear clinical signs of parvovirus infection including enteritis, severe bloody diarrhea, vomiting and fever, and PCR-positive for CPV2 was treated for 2 weeks twice daily with 10 mg/kg amantadine HCI. Unexpectedly, clinical signs improved from day 3 onwards and the dog recovered completely after 2 weeks of treatment.

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Abstract

La présente invention concerne des composés destinés à être utilisés dans un procédé pour le traitement ou la prévention d'infections par le parvovirus chez les êtres humains et les animaux à sang chaud, y compris les infections par le virus de la panleucopénie féline (FPV) dans les félidés, les infections par le parvovirus canin de type 2 (CPV -2) chez les canins, les infections par le virus minute de souris (MVM) dans les souris et les infections par le parvovirus B19 chez l'homme.
PCT/EP2013/053526 2012-02-24 2013-02-22 Composés pour le traitement d'une infection à parvovirus WO2013124403A1 (fr)

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RU2014138131A RU2014138131A (ru) 2012-02-24 2013-02-22 Соединения для лечения парвовирусной инфекции
US14/380,515 US20150018427A1 (en) 2012-02-24 2013-02-22 Compounds for treating parvovirus infection
BR112014020597A BR112014020597A2 (pt) 2012-02-24 2013-02-22 compostos para tratar infecção por parvovírus
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JP2014558115A JP2015508091A (ja) 2012-02-24 2013-02-22 パルボウイルス感染症を治療するための化合物
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